DESCRIPTION: The principal goal of this research program is to develop a practical synthetic approach to the spongipyrans, a new family of architecturally unique bis-spiroketal macrolides that possess extraordinary antitumor activities. Three research groups have isolated members of the spongipyran family that they designated the spongistatins 1-9, cinachyrolide A, and the altohyrtins A, B and C, respectively. The spongistatins appear to be the most potent inhibitors of cancer cell growth discovered to date. The initial synthetic target is spongistatin 1; none of the spongipyran structures have been verified by degradation or X-ray analysis. Accordingly, the initial objectives are two-fold: (A) to define the complete relative and absolute stereochemistry of spongistatin 1 by chemical degradation and synthesis. To this end, a working collaboration has been established with Professor George Pettit (Director of the Cancer Research Institute, Arizona State University), the discoverer of spongistatins, who has already provided natural spongistatin 1 for degradation; and (B) to devise a highly efficient strategy for the total synthesis of the spongistatins. Apart from the anticipated pharmaceutical impact, success in this venture will constitute a major achievement for complex molecule synthesis in general. This program also will serve as excellent training for graduate and postdoctoral students. In conjunction with the proposed synthesis of the spongistatins, (C) a new methods will be investigated for the rapid construction of spiroketals via the one-pot unsymmetrical bis-coupling of dithianes with epoxides and (D) a new reagent will be developed for asymmetric 2-haloallylboration. The former builds upon the PI's extensive experience with dithiane couplings in the assembly of complex structures; the latter holds promise as a valuable extension of the Brown allylboration chemistry.